Orally active semisynthetic cephalosporin

Mechanism of Action. The drug has been specifically designed as an orally active semisynthetic cephalosporin. Importantly, there are two vital reasons that are solely responsible for the oral inactivation of cephalosporins, namely ... 

In the preparation of semisynthetic cephalosporins, the following improvements are sought (a) increased acid stability, (b) improved pharmacokinetic properties, particularly better oral ab.sorption, ic) broadened antimicrobial spectrum. (d) increased activity agaiast resistant microorganisms (as a result of resistance to enzymatic destruction, improved penetration. increased receptor affinity, etc.), (e) decreased allergenicity, and (f) increased tolerance after parenteral administration. 

If a drug fails to meet present day standards because of low in vitro potency, metabolic, or chemical instability, poor oral absorption or high degree of serum and tissue binding, experience teaches that the prospects for improvement via structural modification are good—if systematic structural modification with retention of biological activity is feasible. The clinically established semisynthetic cephalosporins, rifamycin SV and rifampicin represent precisely this kind of improvement, while laboratory data indicate that it has also been achieved in the coumermycin series as well (96, 97). 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporins, a number of which are synthesized by acylation of fermentation-derived 7-armnocephalosporanic acid, are an example. Two orally active cephalosporins called cefroxadine and cephalexin are produced by a synthetic ting-expansion of penicillin V. 

SEMISYNTHETIC CEPHALOSPORINS. III. SYNTHESIS AND STRUCTURE ACTIVITY RELATIONSHIPS OF NOVEL ORALLY ACTIVE 7-[4-HYDROXY-3-(SUBSTITUTED METHYL)PHENYL]-ACETAMIDO-3-CEPHEM-4-CARBOXYLIC ACIDS... 

The majority of the semisynthetic cephalosporins are not effective when administered orally. The main exceptions are cephalexin and cephradine, and recently reported compounds such as cefaclor, cefadroxyl and cefatrizine. In view of the fact that oral activity is observed primarily in derivatives of a-amino aryl acetic acids, we designed our synthetic course on the basis of modification of the aryl part of a readily available a-amino acid, in such a way that initial functionalization of the aromatic ring would provide a "handle , which could in turn be easily converted into a variety of functional groups. The second in5)ortant criterion was the necessary optical activity of the amino acids. In order to avoid the resolution of each individual compound thus obtained, it was deemed important to start with an optically active amino acid whose modification would proceed without racemization. These two requirements were fulfilled upon chloromethylation of D-a-amino-4-hydroxyphenyl acetic acid 1. ... 

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